Martin Spielberger

Neopterin as a new biochemical marker for diagnosis of allograft rejection. Experience based upon evaluation of 100 consecutive cases.

The use of daily urinary neopterin evaluation to detect immunological complications has been tested in 96 consecutive cadaveric kidney recipients, three liver recipients, and one pancreas recipient. In 29 of these patients an immunologically uncomplicated posttransplant course was associated with stable or low neopterin levels, or both. In only 5% of daily determinations on these patients were increasing or high neopterin levels seen. On the other hand, major immunological complications, such as acute rejection episodes (38 cases), viral infections (17 cases), or both problems (8 cases), were preceded by increasing or high neopterin levels or both--on the average by one day. Withdrawal of cyclosporine was also found to be followed by increase of urinary neopterin levels. Neopterin evaluation enabled reliable and accurate prediction of immunological complications in 95% of patients with acute rejections and in 100% of patients with viral infections. It thus appears that daily assessment of urinary neopterin levels represents a useful tool for biochemical detection of immunological complications in allograft recipients.

Posttransplant neopterin excretion in renal allograft recipients--a reliable diagnostic aid for acute rejection and a predictive marker of long-term graft survival.

During the immediate posttransplant period, daily measurements of urinary neopterin, which is produced by stimulated macrophages, were evaluated in 294 consecutive recipients of renal allografts for their diagnostic value in acute graft rejection. The ability of mean and peak neopterin excretion values to predict long-term graft survival was analyzed on the basis of an eight-year follow-up. Immunosuppressive therapy (cyclosporine ± prednisone versus azathioprine + prednisone) and initial nonfunction did not influence neopterin exeretion. In patients with rejection episodes and in those with infections, neopterin levels were significantly increased. Diagnostic sensitivity and specificity with regard to rejection diagnosis were assessed for different levels of neopterin. By statistical analysis, a significant association between increased neopterin and higher risk of rejection was found, which was particularly pronounced in patients receiving cyclosporine. Increase in neopterin excretion preceded clinical rejection diagnosis by up to four days. Peak neopterin values above 800 μmol/mol urinary creatinine observed during the posttransplant period, were associated with significantly poorer graft survival. A multivariate analysis showed that peak neopterin levels, age of patients, and early posttransplant presence/absence of acute rejection were significant and independent joint predictors for long-term graft survival. Measurement of neopterin can be of help as an additional marker in early diagnosis of renal allograft rejection, and high neopterin values during the initial posttransplant period are associated with poorer long-term graft survival.

β2-Microglobulin: a prognostic parameter for graft survival after renal transplantation

Abstract The determination of β 2 -microglobulin has recently been proposed as a promising diagnostic method to monitor the state of renal allografts. Elevated levels of β 2 MG in the serum and/or urine allow the substantiation of the diagnosis of an acute graft rejection and are helpful in distinguishing acute tubular necrosis from a rejection reaction (1). In this paper, the usefulness of β 2 MG serum levels is evaluated, not only during the immediate post-operation phase but also for the long-term prognosis of renal allografts. The immunosuppression treatment included methylprednisolone and azathioprine in all the presented patients. The data indicate that a rapid normalization of β 2 MGSL within 6 days, even if the decrease is interrupted by reelevation due to acute rejection episodes or inflammatory diseases, represents a good longterm prognosis for kidney allografts.

Use of Donor-Specific T-Cell Lines for Monitoring of Human Allograft Recipients

Donor-specific and highly cytotoxic T-cell lines (TCL) as well as lectin-induced TCL were established from pretransplant lymphocytes of 6 cadaveric renal allograft recipients. These TCL were used in the 125I-staphylococcus protein A assay to detect IgG antibodies in pre- and posttransplant sera of these patients preferentially binding to autologous donor-specific TCL. Such antibodies were detected in pretransplant sera from 4 of these 6 allograft recipients. Antibody levels in these 4 patients and in 1 additional case who became positive after transplantation further increased during acute cellular rejection episodes. They disappeared after successful treatment but remained elevated until transplantectomy for treatment of irreversible rejection in 1 case. IgG antibodies binding to autologous lectin-induced TCL were detected in only 1 patient and exhibited a pattern clearly different from those binding to donor-reactive TCL. Although attempts to define the antigenic specificity of the autoantibodies binding to donor-specific TCL by genetical and biochemical means has remained unsuccessful so far, the demonstration of their relationship to in vivo expansion of donor-reactive immune cells deserves further attention.

Evaluation of spontaneous lymphocyte proliferation by single cell autoradiography in human allograft recipients

Spontaneous lymphocyte proliferation was studied in 22 patients receiving cadaveric renal transplants before and at various times after grafting. Prophylactic immunosuppression consisted of CyA and prednisone. Spontaneous lymphocyte proliferation was evaluated in a total of 500 single cell autoradiographs after short term in vitro incubation with [3H]TdR. In 13 patients without clinical problems a transitory increase of lymphocyte labeling indices to approximately five times the pretransplant levels was observed. The failure to detect such increments in two patients receiving optimally matched grafts suggested that this early proliferative lymphocyte peak might be caused by in vivo recognition of major histocompatibility antigens. Much higher labeling indices were detected in close temporary association with acute cellular rejection (4 cases), severe infections and withdrawal of CyA (3 cases) and venous thrombosis (1 case). Only moderately elevated numbers of spontaneously proliferating lymphocytes were seen in one patient with a reversible vascular rejection episode. It appears that assessment of spontaneous lymphocyte proliferation is capable of discriminating on a quantitative level between patients with and without clinical problems such as acute cellular rejection and infection.